In the synthesis of biotin or of so-called decarboxybiotin (in which the carboxy group of biotin has been replaced by a methyl group), the present invention provides an improved, more direct method for the conversion of a 1,3-diacyl-4-(bromomethyl)-5-[(5-alkoxycarbonylpentanoyl) or hexanoyl]-4-imidazolin-2-one, of the formula ##STR2## wherein R is (C.sub.1 -C.sub.5)alkanoyl or (C.sub.2 -C.sub.5)alkoxycarbonyl and X is methyl or (C.sub.2 -C.sub.5)alkoxycarbonyl, to a 1,3-diacyl-4-[(4-alkoxybutanoyl) or pentanoyl]-1H,3H-thieno(3,4-b)imidazoyl-2-one of the formula ##STR3## wherein R and X are as defined above. The present method proceeds via the Bunte salt of the formula ##STR4## wherein R and X are as defined above and Y represents an alkali metal (lithium, sodium or potassium).
Heretofor Mukaiyama et al., Japanese Kokai No. 75-88,086 (Chemical Abstracts 84:31061i) transformed compound (I) wherein R is acetyl and X is ethoxycarbonyl by reaction of (I) with thiolacetic acid, forming the 4-(acetylthiomethyl) derivative, followed by cyclization to the thienoimidazolone in acetic acid in the presence of dry HCl.sup.-- with concurrent hydrolysis of the ethyl ester and loss of the acetyl groups. The latter groups must be replaced in an added step because of their importance in facilitating the next stage (hydrogenation) of biotin synthesis. In like manner, Zav'ylov et al. [A], Izv. Akad. Nauk. SSSR, Ser. Khim. 1973, pp. 1679-1681 (Chem. Abstracts 79:105143h) have cyclized the same 4-(acetylthiomethyl) derivative with aqueous NaOH followed by aqueous HCl, again with concurrent hydrolysis and loss of both acetyl groups; see also Russian patent No. 579,767 where cyclization is accomplished with p-toluenesulfonic acid in methanol, again with loss of both acetyl groups (now with conversion to methyl ester rather than hydrolysis to the carboxylic acid).
Similarly, Zav'yalov et al. [B], Isv. Akad. Nauk. SSSR, Ser. Khim. 1980, pp. 1943-1945 (Chem. Abstracts 94:15640y) transformed the compound (I) wherein R is acetyl and X is methoxycarbonyl by reaction of (I) with N-benzoylthiourea to form the isothiuronium salt [4-CH.sub.2 SC(.dbd.NH)NHCOC.sub.6 H.sub.5.HBr], followed by cyclization in methanol-p-toluene sulfonic acid, again with loss of both acetyl groups. The highly noxious odor problems associated with this, as well as the above processes employing acetylthio intermediates, represents another major disadvantage of these processes--a disadvantage which is not shared by the present process.
Although Zav'yalov et al. [B] reacted 4-(chloromethyl)-5-(5-ethoxycarbonylpentanoyl)-4-imidazolin-2-one with sodium thiosulfate in ethanol at room temperature, followed by addition of p-toluenesulfonic acid and boiling, to form a poor yield 4-(4-ethoxycarbonylbutanoyl)-1H,3H-thieno[3,4-d]imidazol-2-one requiring chromatographic purification, they report that attempted, analogous cyclization of the acetylated compound of the above formula (III), wherein R is acetyl, X is ethoxycarbonyl and Y is sodium, was not successful at all, there being formed instead the deacetylated methyl ether: ##STR5## Zav'yalov et al. offer no specific experimental method for preparation, isolation or characterization of the diacetylated thiosulfate salt derivative which they attempted to cyclize.